In this project we will focus on defining the process of elastolytic injury of pulmonary cells and their extracellular matrix. In particular, we aim to identify the function of heparan sulfate proteoglycans (HSPGs) as regulators of elastolysis and modulators of the cellular response to injury. In addition, we will investigate the consequences of elastase injury to the extracellular matrix on vascular endothelial growth factor (VEGF) storage, release, and activity. Our previous studies have implicated proteoglycans as central mediators of elastase damage to pulmonary cells and matrix. Specifically, we have shown that HSPGs modulate growth factor storage, release, and transport within the matrix;moreover, we have also found that elastase-generated HSPG fragments feed back to inhibit elastase and that elastase leads to increased nuclear HSPGs, reduced histone acetylation, reduced tropoelastin expression, and release of VEGF fragments. We plan to expand our studies to focus on the function of released fragments of HSPGs, the specific HSPGs, syndecans 1 and 4, and VEGF.
Our specific aims are to: 1) Identify the mechanisms and functional consequences of HSPG inhibition of elastase activity. 2) Define the mechanisms and functional consequences of elastase release of VEGF from pulmonary cells and matrix. 3) Determine the role of HSPGs in mediating the response of lung fibroblasts to elastase injury. We will use a combination of biochemical, molecular, and biophysical approaches in conjunction with cell culture and animal studies utilizing syndecan knock out mice to investigate the complex process of lung injury and repair. Ultimately, these studies will provide critical insight into the cascade of events initiated by elastolytic injury and the subsequent development of emphysema. Project Narrative: Chronic Obstructive Pulmonary Disease, which includes emphysema, is the fourth leading cause of death in the United States, accounting for more than 120,000 deaths in 2002. To develop effective therapies for this """"""""quiet killer"""""""" a more complete understanding of the underlying cellular and molecular causes is required. In the present project, we propose to identify new critical components of how the lung responds, appropriately and inappropriately, to a specific type of injury (elastolysis) so that this information might provide insight toward the development of therapies that aim to assist lung repair and avoid disease.
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